Multiple sclerosis is a presumed autoimmune disease of the central nervous system. In the past three years we have studied immunoregulatory T-cells in MS using monoclonal antibodies and have found perturbations of suppressor/cytotoxic cells that appear to correlate with disease activity. In addition, we have found that various forms of immunotherapy may affect the course of multiple sclerosis; specifically, the use of short courses of high dose cyclophosphamide, which presumably acts by destroying immunocompetent lymphocytes. The current proposal is an extension of these studies, applying T-cell cloning techniques and limiting dilution analysis for a more sophisticated analysis of T-cell immunoregulation in multiple sclerosis. In addition, immunologic studies in patients currently undergoing a variety of immunotherapeutic regimens will be continued. Investigation of immunoregulatory T-cells in MS will include the following: 1) limiting dilution analysis of T-cells in peripheral blood and cerebrospinal fluid in order to correlate T-cell phenotype with functional characteristics (viz., cytotoxic, suppressor and helper function); 2) analysis of white matter reactive clones in peripheral blood and cerbrospinal fluid to a series of defined white matter antigens; 3) investigation of autoreactive T-cell clones; 4) analysis of T-cell activaton antigens; and 5) immunohistochemical analysis of lymphocytes in multiple sclerosis plaques. Clinical studies will involve investigation of the effect of other immunotherapeutic regimens on immune parameters in MS. This proposal represents a revised competitive renewal as follows: Clinical studies treating multiple sclerosis patients with monoclonal anti-T12 antibody have been deleted from this revised proposal and new data and investigations related to T-cell activation antigens, limited dilution analysis of T-cell clones, and autoreactive T-cells have been incorporated.